The objective of this grant is to contribute to a better understanding of the regulation of mood under normal circumstances as well as the mechanisms underlying depression and antidepressant treatment. For the first 14 years of the grant, our focus was quite broad. We contributed to an appreciation of the role of several classes of signaling proteins in these phenomena. Over the past 4 years, we have greatly focused the grant on one of these signaling proteins, namely, the transcription factor DFosB. DFosB, a member of the Fos family, is induced in a region- and cell type-specific manner in brain by many types of chronic stimuli, including chronic consumption of natural rewards, chronic stress, or chronic antidepressant treatments. Unlike all other Fos family proteins, which exhibit a very short half-life, DFosB is a highly stable protein. As a result, once it accumulates in brain it can persist for weeks or months and thereby mediate relatively long-lived plasticity to the original chronic stimulus. This grant focuses on the consequences of DFosB induction in the nucleus accumbens (NAc) and certain other brain areas. In the NAc, chronic exposure to stress or antidepressants induces DFosB in both dynorphin+ and enkephalin+ neurons, while natural rewards do so selectively in dynorphin+ neurons. Using a combination of inducible bitransgenic mice and viral-mediated gene transfer to overexpress DFosB or a dominant negative antagonist, we have evidence that DFosB induction in this brain region mediates an antidepressant-like response in the social defeat, forced swim, and learned helplessness tests. DFosB mediates a similar antidepressant-like effect in other brain areas of interest. Work is currently underway to better understand the behavioral phenotype mediated by DFosB in these regions in models of natural rewards, stress, and antidepressant responses. As a transcription factor, DFosB presumably produces these behavioral effects through the regulation of other genes. Accordingly, a related major goal of this grant is to identify putative target genes for DFosB in these brain regions, including the use of chromatin remodeling assays to help identify DFosB targets as well as to provide detailed insight into the underlying molecular mechanisms involved. Our work to date thus suggests that induction of DFosB in the NAc and other brain areas may represent a positive adaptation to stress, which enhances motivation for natural rewards and contributes to an individual's ability to actively cope with adverse circumstances. In some of these regions, where DFosB is also induced by antidepressants, the protein may contribute to the therapeutic mechanism of action of these treatments. The proposed studies will further evaluate these hypotheses and improve our understanding of stress and antidepressant responses.